Sleep apnoea and incident malignancy in type 2 diabetes
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ORIGINAL ARTICLE
SLEEP
Sleep apnoea and incident malignancy in
type 2 diabetes
Sarah Driendl1,9, Michael Arzt1,9, Claudia S. Zimmermann2, Bettina Jung3,4,
Tobias Pukrop5, Carsten A. Böger3,4, Sebastian Haferkamp6, Florian Zeman7,
Iris M. Heid8 and Stefan Stadler1
Affiliations: 1Dept of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany. 2Dept of
Internal Medicine I, University Hospital Regensburg, Regensburg, Germany. 3Dept of Nephrology, University
Hospital Regensburg, Regensburg, Germany. 4Dept of Nephrology, Traunstein, Germany. 5Dept of Internal
Medicine III, University Hospital Regensburg, Regensburg, Germany. 6Dept of Dermatology, University
Hospital Regensburg, Regensburg, Germany. 7Centre of Clinical Studies, University Hospital Regensburg,
Regensburg, Germany. 8Dept of Genetic Epidemiology, University Hospital Regensburg, Regensburg,
Germany. 9These authors contributed equally.
Correspondence: Stefan Stadler, Dept of Internal Medicine II, University Medical Center Regensburg, Franz-
Josef-Strauss-Allee 11, 93055 Regensburg, Germany. E-mail: stefan.stadler@ukr.de
ABSTRACT
Background: Sleep apnoea and type 2 diabetes (T2D) have been linked to malignancy. The aim of the
present study was to evaluate the association between sleep apnoea and incidence of malignancy in
patients with T2D.
Methods: The DIACORE (DIAbetes COhoRtE) study is a prospective, population-based cohort study in
T2D patients. In the sleep disordered breathing substudy, the apnoea–hypopnoea index (AHI), oxygen
desaturation index (ODI) and percentage of night-time spent with a peripheral oxygen saturation ofSLEEP | S. DRIENDL ET AL.
Introduction
Sleep apnoea is a highly prevalent disorder characterised by repetitive apnoeas and hypopnoeas and
arousals from sleep. The prevalence of moderate-to-severe sleep apnoea (defined as apnoea–hypopnoea
index (AHI) ⩾15 events·h−1) is up to 49% in males and 23% in females, and it has increased substantially
over the past two decades [1, 2]. Sleep apnoea is strongly associated with cardiovascular and metabolic
morbidity and mortality [3, 4]. Sleep apnoea leads to intermittent hypoxaemia and sleep fragmentation,
and causes sympathetic nervous system activation, oxidative stress and systemic inflammation [5–8]. Sleep
apnoea and intermittent hypoxaemia have been linked to an increased incidence [9–12], growth,
angiogenesis, chemoresistance and radioresistance in tumours [13–16]. Experimental studies have shown
that intermittent hypoxaemia can lead to a faster and more invasive tumour growth as well as metastasis
in animal studies [17–19]. There was an association between sleep apnoea and increased tumour mortality
in clinical studies [20]. Until now, clinical studies investigating the association between sleep apnoea and
incidence of malignancy have shown inconsistent results [21, 22]. When such evidence is documented in
cohort studies where incident cancer is assessed, this could point to new paths of cancer prevention
through early diagnosis and treatment of sleep apnoea or nocturnal hypoxaemia.
Type 2 diabetes mellitus (T2D) is an important hazard, with prevalence rates rising worldwide [23, 24].
T2D and sleep apnoea are each likely to contribute to the development of the other [25] and show high
co-occurrence rates [26–29]. T2D has also been linked to an increased risk of incident malignancies [30].
This is the first study to evaluate the association between sleep apnoea and incidence of malignancy in a
sample of patients with T2D.
Methods
Study design
The investigated patients were participants of the DIACORE (DIAbetes COhoRtE)-SDB (sleep disordered
breathing) substudy [31]. DIACORE is a two-centre prospective and longitudinal cohort study of T2D
patients of European descent [32]. The DIACORE study was originally designed to determine incident
micro- and macrovascular T2D complications, malignancy and hospitalisation [32]. As the substudy was
conducted only at the Regensburg Clinical Study Centre (Regensburg, Germany), all participants from the
Regensburg centre were invited to take part in the DIACORE-SDB substudy. 492 (16%) patients did not
agree to participate. Other patients did not participate for the following reasons: recruiting centre not
offering SDB monitoring, current use of positive airway pressure (PAP) therapy, study termination and
SDB monitoring not performed (figure 1).
DIACORE (DIAbetes COhoRtE)
patients
n=3000
Not included in SDB substudy n=1585 (53%)
Recruiting centre not offering SDB monitoring n=706
SDB monitoring denied by patient n=492
Current use of positive airway pressure therapy n=121
Study termination (withdrawal of consent, death) n=119
SDB monitoring not performed n=147
DIACORE-SDB substudy
sample
n=1415 (47%)
Excluded n=176 (12%)
Incomplete data on SDB monitoring data n=82
Lost to follow-up n=31
Withdrawal of consent n=31
Malignancy diagnosis before baseline visit n=32
Analysed sample
n=1239 (88%)
No incident malignancy Incident malignancy
n=1160 (93.6%) n=79 (6.4%)
FIGURE 1 Study flow chart. SDB: sleep disordered breathing.
https://doi.org/10.1183/23120541.00036-2021 2SLEEP | S. DRIENDL ET AL.
The participants were subjected to a standardised online questionnaire, blood sampling and physical
examination, and were invited to re-examinations every 2 years. Assessment of sleep apnoea was
performed using a two-channel ambulatory monitoring device (ApneaLink; ResMed, Sydney, Australia).
The DIACORE-SDB substudy started in November 2011 and patients were followed-up every 2 years until
April 2018.
The protocol, data protection strategy and study procedures were approved by the ethics committees of
the participating institutions and in accordance with the Declaration of Helsinki. Patients participated in
the DIACORE study only after providing written consent. The study protocol has been described
previously [32]. The study is registered at the German Clinical Trials Register (https://drks.de/; identifier
number DRKS00010498) and at the International Clinical Trials Registry Platform of the World Health
Organization.
Study population
All T2D patients living in the regions around Regensburg and Speyer were eligible for participation in the
DIACORE study (figure 1) [32]. The recruitment process has been described previously [32]. Further
inclusion criteria were as follows: ability to fully understand the study information; ability to give written
informed consent; age ⩾18 years; and self-reported Caucasian ethnicity [32]. Exclusion criteria included a
history of active malignancy within the past 5 years ( prostatic cancer within the past 2 years);
haemochromatosis; history of pancreoprivic or self-reported type 1 diabetes mellitus; acute infection or
fever; pregnancy; chronic viral hepatitis or HIV infection; presence of autoimmune disease potentially
affecting kidney function; and chronic renal replacement therapy [32]. For the DIACORE-SDB substudy,
participants were included if they consented to perform sleep apnoea monitoring and excluded if they
currently used PAP therapy [31].
Alcohol intake (number of drinks per week), smoking status (current, former or never), socioeconomic
status (according to the Robert Koch Institute, Germany [33], subdivided into four groups ranging from 1
(lowest) to 4 (highest) and including educational level, professional qualification and income) and physical
activity (defined as light activity at least three times per week) were evaluated by standardised
questionnaires. Subjective daytime sleepiness was assessed using the validated Epworth Sleepiness Scale.
Patients were asked to rank how likely it was for them to fall asleep in various common situations [31].
Scores range from 0 (least sleepy) to 24 (sleepiest). Excessive daytime sleepiness is defined as a score of ⩾11.
Assessment of sleep apnoea
Ambulatory sleep apnoea monitoring was conducted using a validated device [34, 35] (ApneaLink), as
described previously [31]. The participants were instructed on the use of the device by trained personnel
in a standardised manner [31]. Nasal flow and pulse oximetry were measured. AHI was calculated as the
mean number of apnoea and hypopnoea events per hour of recording time. Oxygen desaturation index
(ODI) measured the mean number of respiratory events per hour where blood oxygen level dropped by
4% in comparison with immediately preceding basal value. The percentage of the total recording time with
a peripheral oxygen saturation below 90% (tsat90%) was documented. The standard settings of the
monitoring device were used for the definitions of apnoea, hypopnoea and desaturation [36]. Due to the
lack of a chest band, it was not possible to differentiate between obstructive and central apnoea.
All patients were informed about the results of sleep apnoea monitoring, but further diagnosis and
treatment was not part of the protocol of DIACORE. Use of PAP treatment during follow-up was
evaluated by standardised questionnaires as part of the protocol of DIACORE. PAP treatment status was
available in 1133 patients.
Assessment of incident malignancy
The incidence of a malignancy, defined as the first diagnosis of a malignant neoplasm at any time between
the sleep apnoea monitoring (starting November 2011) and the last performed DIACORE follow-up visit
(April 2018), was assessed by medical history and medical records at every visit by the DIACORE
end-point committee [32]. Medical documentation was requested up to three times from the patients’
treating physicians and validated by an experienced physician. If a patient-reported end-point could not be
confirmed by available documentation or if adequate medical documentation was not available, then that
end-point was coded as “not validated” and analysed as “no cancer” [32]. Basal cell carcinomas were
excluded from the analysis, as these tumours rarely metastasise and have low mortality.
Statistical analysis
Descriptive data are presented as mean±SD for normally distributed variables and as median and
interquartile range for non-normally distributed variables. Continuous variables were compared by t-test
https://doi.org/10.1183/23120541.00036-2021 3SLEEP | S. DRIENDL ET AL.
and categorical variables by Chi-squared test. AHI, ODI and tsat90% were used as surrogates of sleep
apnoea severity, all as continuous variables and in categories. Sleep apnoea severity categories according
to the AHI were defined asSLEEP | S. DRIENDL ET AL.
TABLE 2 Tumour entities
Total sample 1239
Skin tumours# 20 (25.3)
Prostate carcinoma 9 (11.5)
Colorectal carcinoma 7 (8.9)
Pancreatic carcinoma 7 (8.9)
Breast cancer 5 (6.3)
Pulmonary carcinoma 5 (6.3)
Malignancy of the haematopoietic and lymphatic system 5 (6.3)
Malignancy of the female genital organ 5 (6.3)
Malignancy of the urinary organ 5 (6.3)
Others¶ 11 (13.9)
Total 79 (100)
Males 728
Skin tumours# 15 (28.3)
Prostate carcinoma 9 (17.0)
Colorectal carcinoma 7 (13.2)
Malignancy of the urinary organ 5 (9.4)
Pulmonary carcinoma 4 (7.5)
Pancreatic carcinoma 3 (5.7)
Malignancy of the haematopoietic and lymphatic system 2 (3.8)
Others¶ 8 (15.1)
Total 53 (100)
Females 511
Skin tumours# 5 (19.2)
Breast cancer 5 (19.2)
Malignancy of the female genital organ 5 (19.2)
Pancreatic carcinoma 4 (15.4)
Malignancy of the haematopoietic and lymphatic system 3 (11.6)
Pulmonary carcinoma 1 (3.8)
Others¶ 3 (11.6)
Total 26 (100)
Data are presented as n or n (%). #: malignant melanomas, squamous cell carcinomas and lentiginous
melanomas (basal cell carcinomas were excluded); ¶: cancer types observed only in few or single persons,
e.g. liver tumour, parotid tumour, meningioma.
p=0.294), respectively. Hazard ratios for the incidence of a malignancy in dependency on continuous and
dichotomised sleep apnoea parameters are given in tables 3 and 4; all analyses were adjusted for potential
confounders such as age, sex, BMI, smoking status, alcohol intake, socioeconomic status and HbA1c.
There was no association between any of the six sleep apnoea parameters and incident cancer in the entire
TABLE 3 Adjusted hazard ratios (HRs) for the incidence of malignancy in 1239 patients with
type 2 diabetes during a median follow-up of 2.7 years (number of events 79)
Adjusted HR (95% CI)# p-value
AHI events·h−1
AHI (continuous) 1.01 (0.99–1.03) 0.416
AHI ⩾30 1.30 (0.64–2.62) 0.473
ODI events·h−1
ODI (continuous) 1.00 (0.98–1.02) 0.799
ODI ⩾30 1.24 (0.57–2.68) 0.584
tsat90%
tsat90% (continuous) 1.00 (1.00–1.01) 0.395
tsat90% ⩾10.4% 1.59 (0.94–2.68) 0.085
HRs calculated using Cox proportional hazards regression analysis. The multivariable analyses were
adjusted for sex, age, body mass index, smoking status, alcohol intake, socioeconomic status and HbA1c.
AHI: apnoea–hypopnoea index; ODI: oxygen desaturation index; tsat90%: percentage of night-time spent with
oxygen saturationSLEEP | S. DRIENDL ET AL.
TABLE 4 Adjusted hazard ratios (HRs) for the incidence of malignancy in 1239 patients with type 2 diabetes during a median
follow-up of 2.7 years stratified by sex and age
Males Females ⩾70 yearsSLEEP | S. DRIENDL ET AL.
a) 1.0 AHISLEEP | S. DRIENDL ET AL.
a) i) 1.0 ii) 1.0 AHISLEEP | S. DRIENDL ET AL.
TABLE 5 Association of sleep apnoea and incidence# of malignancy, comparison of existing studies
First author Population T2D % Study design Follow-up Sleep Main Main findings Key
(year) [ref.] n (% years apnoea outcomes limitations
female) diagnosis
Sleep apnoea
diagnosis with
PSG or PG
Prospective
DRIENDL 1239 100 Prospective 2.7 PG Cancer Association Use of PG
(2020; (41) cohort study incidence between AHI
present (n=79) ⩾30 events·h−1
study) and cancer
incidence in
females
MARSHALL 390 3 Prospective 20 PG Cancer Association Small
(2014) [39] (26) cohort study incidence between population
(n=125) elevated RDI Lack of control
(⩾15 events·h−1) of some
and cancer cancer risk
incidence factors
Lack of
information on
PAP therapy
Retrospective
JUSTEAU 8748 15 Retrospective 5.8 PSG, PG Cancer Association Lack of control
(2020) [40] (36) cohort study, incidence between of some
multicentre (n=718) nocturnal cancer risk
hypoxaemia factors
(tsat90% >13%) Partial use of
and cancer PG
incidence
CAMPOS- 4910 n/s Retrospective 4.5 PSG (32%), Cancer Association Lack of control
RODRIGUEZ (33) cohort study, PG (68%) incidence between severe of some
(2013) [9] multicentre (n=261) OSA (tsat90% cancer risk
>12%) and factors
cancer Major use of
incidence, PG
limited to male
patients
57 events·h−1 cancer risk
and cancer factors
incidence for Lack of
patients information onSLEEP | S. DRIENDL ET AL.
TABLE 5 Continued
First author Population T2D % Study design Follow-up Sleep Main Main findings Key
(year) [ref.] n (% years apnoea outcomes limitations
female) diagnosis
Meta-analysis
SHANTHA 112 228 4–22 Meta-analysis, 4.5–20 PSG, PG Cancer Patients with
(2015) [21] (26–100) five studies incidence SDB had a
(n=864) nearly 50%
greater overall
cancer risk
compared with
patients
without SDB
ZHANG (2017) 86 460 n/s Meta-analysis, 4.5–20 PSG, PG Cancer OSA was not
[22] (26–38) six studies incidence independently
(n=965) associated with
cancer
incidence
OSA diagnosed
according to
ICD-9 or
symptoms
Prospective
CHRISTENSEN 8783 n/s Prospective 13 Symptoms Cancer No association OSA diagnosis
(2013) [43] (55) cohort study of OSA incidence between based on
(n=1985) symptoms of symptoms
OSA and Lack of
cancer information on
incidence PAP therapy
Retrospective
GOZAL (2016) 5.6 million 14 in Retrospective 3.2–3.9 According Cancer Elevated risk Potential bias
[11] (50) OSA-group cohort study to incidence for malignant by use of
ICD-9-CM (n=167 022) melanoma and administrative
kidney and claims
pancreatic database
cancer for Lack of control
patients with of some
OSA cancer risk
Lower risk for factors
colorectal,
breast and
prostate cancer
for patients
with OSA
SILLAH (2018) 34 402 n/s Retrospective 5.3 According Cancer Elevated risk Lack of control
[12] (43) cohort study to incidence for malignant of some
ICD-9-CM (n=1575) melanoma and cancer risk
kidney, uterine factors
and breast Lack of
cancer for information on
patients with PAP therapy
OSA
Lower risk for
colorectal and
lung cancer for
patients with
OSA
T2D: type 2 diabetes mellitus; PSG: polysomnography; PG: polygraphy; OSA: obstructive sleep apnoea; ICD-9-CM: International Classification
of Diseases, 9th Revision, Clinical Modification; AHI: apnoea–hypopnoea index; RDI: respiratory disturbance index; n/s: not specified; PAP:
positive airway pressure; SDB: sleep disordered breathing; tsat90%: percentage of night-time spent with oxygen saturationSLEEP | S. DRIENDL ET AL.
125 events observed during a follow-up time of 20 years, showed that participants with moderate to severe
sleep apnoea had a 2.5-fold elevated risk of an incident malignancy, but there were no differences between
males and females. However, hazard ratios for females were elevated but not statistically significant,
probably because of a small sample size, as the analysis had only five females in the moderate-to-severe
OSA group [39].
Even meta-analyses found inconsistent results when investigating the association between sleep apnoea
and the incidence of malignancy. Whereas SHANTHA et al. [21] found a 50% greater overall cancer risk
compared to patients without sleep apnoea, ZHANG et al. [22] found that sleep apnoea was not associated
with incidence of malignancy (table 5). Other studies examining overall malignancy and site-specific
cancer observed that sleep apnoea was only associated with specific cancer types such as malignant
melanoma, kidney, pancreatic, uterine and breast cancer [11, 12] (table 5). Reasons for the inconsistency
of these studies could be limited study power, retrospective design, poor control of cancer risk factors and
potential bias by use of administrative claims database (table 5).
Different pathophysiological mechanisms were suggested to explain the association between sleep apnoea
and incident malignancy, such as intermittent hypoxaemia and sleep fragmentation resulting in oxidative
stress, systemic inflammation and immunodeficiency [16, 44]. These mechanisms can contribute to
changes in tumour biology, accelerated tumour growth and progression of existing tumours including
metastasis [16]. We found an association of sleep apnoea and incident malignancy only in females, but not
in males. One reason could be that females are more likely to have regular physician’s visits and therefore
are more likely to receive a malignancy diagnosis [45, 46].
In our study, skin tumours were the most common malignancy (n=20, 25% of all neoplasms). This
observation differs from the expected distribution of tumours, in which prostate, breast, lung and
colorectal cancer would be the most frequent tumours [37]. Studies found a hypoxic microenvironment of
the skin contributing to melanocyte transformation [47] and a significantly higher incidence of
melanomas in patients with sleep apnoea [11, 12]. However, we lacked statistical power to examine this
association. Sensitivity analyses of the association between measures of sleep apnoea and incidence of
malignancy without nonmelanotic skin cancers show similarly increased hazard ratios in females
(supplementary tables S1 and S2).
There is evidence that PAP treatment may have a moderating role in patients with sleep apnoea and in
neoplasm-related pathways [48–50]. In the present study, there was no difference in malignancy incidence
between patients with and without PAP therapy among patients with at least mild sleep apnoea, nor
among patients with moderate-to-severe sleep apnoea. This should not be interpreted as a lack of efficacy
in PAP therapy, as the number of events in the PAP therapy group was very low (n=5 in both analyses).
Furthermore, because we consider sleep apnoea to be a chronic disease with intermittent hypoxaemia and
other consequences of the disorder likely to have been present for several years before, recent treatment
would probably not immediately affect the outcome.
Strengths of our study include the prospective study design and detailed phenotyping at baseline, which
ensures wide and complete information about lifestyle and socioeconomic factors of the participants,
enabling adjustment for the primary known cancer-related risk factors. Furthermore, we only validated
cancer diagnoses when the self-reported diagnosis could be validated by a medical report.
The present study has the following limitations and thus cannot rule out an association of sleep apnoea
and incidence of malignancy. First, we used a portable respiratory device to diagnose sleep apnoea. Even
though the usage of a home sleep apnoea monitoring device is well established and validated for
assessment of sleep apnoea [35, 51], due to the missing chest band, we could not distinguish between
obstructive and central sleep apnoea. As a result, it is possible that the association we found is only valid
for one of the two forms of sleep apnoea. Nonetheless, as we consider OSA to be the main
pathophysiology linking sleep apnoea and incident malignancy, not excluding central sleep apnoea from
the analysis would most likely confer a conservative bias towards the null, i.e. underestimate the
association between sleep apnoea and the incidence of malignancy. Moreover, in previous studies of
patients with T2D, 99% of the sleep apnoea was obstructive [26, 27]. Furthermore, inaccurate
measurement of the AHI could result from the use of ApneaLink as a monitoring device, which could
decrease the potential association between sleep apnoea and incidence of malignancy. Second, we lacked
the statistical power to examine site-specific malignancies. Thus, we cannot rule out an association
between sleep apnoea and site-specific malignancies such as malignant melanoma [11, 12]. Third, the
median follow-up time of the study is ∼2.7 years, which is a rather short period of time for evaluating
the incidence of malignancies and could decrease the potential association between sleep apnoea and
incidence of malignancy. However, we detected an overall cumulative tumour incidence of 6.4%, which is
largely comparable to previous studies investigating the association between sleep apnoea and incident
https://doi.org/10.1183/23120541.00036-2021 11SLEEP | S. DRIENDL ET AL.
malignancy [9, 10, 41]. It cannot be ruled out that some malignancies were already present at baseline, but
not yet diagnosed. Fourth, the diagnosis of a malignancy was only possible when reported by the
participants in follow-up visits, after which a medical report was obtained to validate the self-reported
diagnosis, potentially introducing bias. Fifth, investigation of patients with T2D could lead to referral bias.
Sixth, the use of Bonferroni-corrected p-values for the female and age-stratified analyses constitutes a
conservative statistical approach. Last, similar to most previous studies evaluating the association of sleep
apnoea and cancer, the present study was not prospectively designed for this research question.
Prospective studies on this topic are warranted.
In summary, there was no association between sleep apnoea and incident malignancy in this sample of
patients with T2D. However, stratified analysis revealed a significant association of sleep apnoea with
incident malignancy in females, but not in males. These findings emphasise the necessity to further
investigate whether there are groups at higher risk for an incident malignancy associated with sleep apnoea
and how T2D influences this association. Therefore, further research including longitudinal analyses and
intervention studies is required to enhance the understanding of the underlying pathophysiological
mechanisms of sleep apnoea on the incidence of malignancies.
Acknowledgements: We thank all participating patients of the DIACORE study. We thank the physicians and health
insurance companies supporting the DIACORE study: Axel Andreae, Gerhard Haas, Sabine Haas, Jochen Manz, Johann
Nusser, Günther Kreisel, Gerhard Bawidamann, Frederik Mader, Susanne Kißkalt, Johann Hartl, Thomas Segiet,
Christiane Gleixner and Christian Scholz (Regensburg, Germany), Monika Schober (Allgemeine Ortskrankenkasse
Bayern), Cornelia Heinrich (Allgemeine Ortskrankenkasse Bayern), Thomas Bohnhoff (Techniker Krankenkasse),
Thomas Heilmann (Techniker Krankenkasse), Stefan Stern (Allgemeine Ortskrankenkasse Bayern), Andreas Utz
(Allgemeine Ortskrankenkasse Bayern), Georg Zellner (Deutsche Angestellten Krankenkasse), Werner Ettl
(Barmer-GEK), Thomas Buck (Barmer-GEK), Rainer Bleek (IKK classic) and Ulrich Blaudzun (IKK classic). We further
thank the study nurses for their excellent work in performing the study visits: Simone Neumeier, Sarah Hufnagel, Isabell
Haller, Petra Jackermeier, Sabrina Obermüller, Christiane Ried, Ulrike Hanauer, Bärbel Sendtner and Natalia
Riewe-Kerow (Centre of Clinical Studies, University Hospital Regensburg, Regensburg). Konstantin Dumann and Britta
Hörmann (PhD students, University Hospital Regensburg) are thanked for their work in performing the study visits.
We thank Helge Knüttel for his exceptional support in literature research.
Author contributions: S. Driendl, M. Arzt and S. Stadler were involved in the conception, hypotheses delineation and
design of the study, the analysis and interpretation of such information, writing the article, and in its revision prior to
submission. C.A. Böger, I.M. Heid and B. Jung are the principal investigators of the DIACORE study, and were involved
in the design of this substudy, the acquisition and interpretation of the data, and the critical revision of the article prior
to submission. C.S. Zimmerman was involved in the acquisition and interpretation of the data, and the critical revision
of the article prior to submission. S. Haferkamp was involved in the interpretation of the data and the critical revision
of the article prior to submission. F. Zeman was involved in statistical data analysis. All authors read and approved the
final manuscript. S. Stadler is the guarantor of this work and, as such, had full access to all data of the study, and takes
responsibility for the integrity of the data and the accuracy of the data analysis. S. Driendl and M. Artz contributed
equally to this work.
Conflict of interest: S. Driendl has nothing to disclose. M. Arzt reports grants from the Else-Kröner Fresenius
Foundation and the Resmed Foundation, grants and personal fees from Philips Respironics and ResMed, and personal
fees from Boehringer Ingelheim, Novartis, Brestotec and NRI, outside the submitted work. C.S. Zimmermann has
nothing to disclose. B. Jung has nothing to disclose. T. Pukrop has nothing to disclose. C.A. Böger reports grants from
KfH Stiftung Präventivmedizin e.V., the Else Kröner-Fresenius-Stiftung and the Dr Robert Pfleger Stuftung during the
conduct of the study. S. Haferkamp has nothing to disclose. F. Zeman has nothing to disclose. I.M. Heid has nothing to
disclose. S. Stadler has nothing to disclose.
Support statement: The DIACORE study has been funded by the KfH Stiftung Präventivmedizin e.V., the
Else-Kröner-Fresenius-Stiftung and the Dr Robert-Pflieger-Stiftung. The DIACORE-SDB substudy has been funded by
ResMed (Martinsried, Germany).
References
1 Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the general population: the
HypnoLaus study. Lancet Respir Med 2015; 3: 310–318.
2 Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep disordered breathing in adults. Am J
Epidemiol 2013; 177: 1006–1014.
3 Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet 2014; 383: 736–747.
4 Drager LF, McEvoy RD, Barbe F, et al. Sleep apnea and cardiovascular disease: lessons from recent trials and need
for team science. Circulation 2017; 136: 1840–1850.
5 Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002; 360: 237–245.
6 Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest
1995; 96: 1897–1904.
7 Yamauchi M, Nakano H, Maekawa J, et al. Oxidative stress in obstructive sleep apnea. Chest 2005; 127:
1674–1679.
8 McNicholas WT. Obstructive sleep apnea and inflammation. Prog Cardiovasc Dis 2009; 51: 392–399.
9 Campos-Rodriguez F, Martinez-Garcia MA, Martinez M, et al. Association between obstructive sleep apnea and
cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med 2013; 187: 99–105.
https://doi.org/10.1183/23120541.00036-2021 12SLEEP | S. DRIENDL ET AL.
10 Brenner R, Kivity S, Peker M, et al. Increased risk for cancer in young patients with severe obstructive sleep apnea.
Respiration 2019; 97: 15–23.
11 Gozal D, Ham SA, Mokhlesi B. Sleep apnea and cancer: analysis of a nationwide population sample. Sleep 2016;
39: 1493–1500.
12 Sillah A, Watson NF, Schwartz SM, et al. Sleep apnea and subsequent cancer incidence. Cancer Causes Control
2018; 29: 987–994.
13 Toffoli S, Michiels C. Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in
tumours. FEBS J 2008; 275: 2991–3002.
14 Liu Y, Song X, Wang X, et al. Effect of chronic intermittent hypoxia on biological behavior and
hypoxia-associated gene expression in lung cancer cells. J Cell Biochem 2010; 111: 554–563.
15 Muz B, de la Puente P, Azab F, et al. The role of hypoxia in cancer progression, angiogenesis, metastasis, and
resistance to therapy. Hypoxia 2015; 3: 83–92.
16 Almendros I, Wang Y, Gozal D. The polymorphic and contradictory aspects of intermittent hypoxia. Am J Physiol
Lung Cell Mol Physiol 2014; 307: L129–L140.
17 Almendros I, Montserrat JM, Ramírez J, et al. Intermittent hypoxia enhances cancer progression in a mouse
model of sleep apnoea. Eur Respir J 2012; 39: 215–217.
18 Perini S, Martinez D, Montanari CC, et al. Enhanced expression of melanoma progression markers in mouse
model of sleep apnea. Rev Port Pneumol 2016; 22: 209–213.
19 Rofstad EK, Gaustad J-V, Egeland TAM, et al. Tumors exposed to acute cyclic hypoxic stress show enhanced
angiogenesis, perfusion and metastatic dissemination. Int J Cancer 2010; 127: 1535–1546.
20 Nieto FJ, Peppard PE, Young T, et al. Sleep disordered breathing and cancer mortality: results from the Wisconsin
Sleep Cohort Study. Am J Respir Crit Care Med 2012; 186: 190–194.
21 Shantha GPS, Kumar AA, Cheskin LJ, et al. Association between sleep-disordered breathing, obstructive sleep
apnea, and cancer incidence: a systematic review and meta-analysis. Sleep Med 2015; 16: 1289–1294.
22 Zhang X-B, Peng L-H, Lyu Z, et al. Obstructive sleep apnoea and the incidence and mortality of cancer: a
meta-analysis. Eur J Cancer Care 2017; 26: e12427.
23 Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes
prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370
country-years and 2.7 million participants. Lancet 2011; 378: 31–40.
24 Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for
2030. Diabetes Care 2004; 27: 1047–1053.
25 Aurora RN, Punjabi NM. Obstructive sleep apnoea and type 2 diabetes mellitus: a bidirectional association. Lancet
Respir Med 2013; 1: 329–338.
26 Laaban J-P, Daenen S, Léger D, et al. Prevalence and predictive factors of sleep apnoea syndrome in type 2
diabetic patients. Diabetes Metab 2009; 35: 372–377.
27 Foster GD, Sanders MH, Millman R, et al. Obstructive sleep apnea among obese patients with type 2 diabetes.
Diabetes Care 2009; 32: 1017–1019.
28 Kroner T, Arzt M, Rheinberger M, et al. Sex differences in the prevalence and modulators of sleep disordered
breathing in outpatients with type 2 diabetes. J Diabetes Res 2018; 2018: 7617524.
29 Resnick HE, Redline S, Shahar E, et al. Diabetes and sleep disturbances: findings from the Sleep Heart Health
Study. Diabetes Care 2003; 26: 702–709.
30 Gallagher EJ, LeRoith D. Obesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol
Rev 2015; 95: 727–748.
31 Stadler S, Zimmermann T, Franke F, et al. Association of sleep-disordered breathing with diabetes-associated
kidney disease. Ann Med 2017; 49: 487–495.
32 Dörhöfer L, Lammert A, Krane V, et al. Study design of DIACORE (DIAbetes COhoRtE) – a cohort study of
patients with diabetes mellitus type 2. BMC Med Genet 2013; 14: 25.
33 Lampert T, Kroll LE, Müters S, et al. Messung des sozioökonomischen Status in der Studie “Gesundheit in
Deutschland aktuell” (GEDA). [Measurement of the socioeconomic status within the German Health Update 2009
(GEDA)]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2013; 56: 131–143.
34 Chen H, Lowe AA, Bai Y, et al. Evaluation of a portable recording device (ApneaLink) for case selection of
obstructive sleep Apnea. Sleep Breath 2009; 13: 213–219.
35 Erman MK, Stewart D, Einhorn D, et al. Validation of the ApneaLink for the screening of sleep apnea: a novel
and simple single-channel recording device. J Clin Sleep Med 2007; 3: 387–392.
36 Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM
Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force
of the American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8: 597–619.
37 Barnes B, Kraywinkel K, Nowossadeck E, et al. Bericht zum Krebsgeschehen in Deutschland 2016. [Report of the
Occurrence of Cancer in Germany]. Berlin, Robert Koch Institute, 2016.
38 Deutsche Diabetes Gesellschaft (DDG), diabetesDE – Deutsche Diabetes-Hilfe. Deutscher Gesundheitsbericht
Diabetes 2016: Die Bestandsaufnahme [German Health Report Diabetes]. Mainz, Kirchheim, 2016.
39 Marshall NS, Wong KKH, Cullen SRJ, et al. Sleep apnea and 20-year follow-up for all-cause mortality, stroke, and
cancer incidence and mortality in the Busselton Health Study cohort. J Clin Sleep Med 2014; 10: 355–362.
40 Justeau G, Gervès-Pinquié C, Le Vaillant M, et al. Association between nocturnal hypoxemia and cancer incidence
in patients investigated for OSA: data from a large multicenter French cohort. Chest 2020; 158: 2610–2620.
41 Kendzerska T, Leung RS, Hawker G, et al. Obstructive sleep apnea and the prevalence and incidence of cancer.
CMAJ 2014; 186: 985–992.
42 Pataka A, Bonsignore MR, Ryan S, et al. Cancer prevalence is increased in females with sleep apnoea: data from
the ESADA study. Eur Respir J 2019; 53: 190091.
43 Christensen AS, Clark A, Salo P, et al. Symptoms of sleep disordered breathing and risk of cancer: a prospective
cohort study. Sleep 2013; 36: 1429–1435.
44 Lévy P, Pépin J-L, Arnaud C, et al. Intermittent hypoxia and sleep-disordered breathing: current concepts and
perspectives. Eur Respir J 2008; 32: 1082–1095.
https://doi.org/10.1183/23120541.00036-2021 13SLEEP | S. DRIENDL ET AL.
45 Shalev V, Chodick G, Heymann AD, et al. Gender differences in healthcare utilization and medical indicators
among patients with diabetes. Public Health 2005; 119: 45–49.
46 Ladwig KH, Marten-Mittag B, Formanek B, et al. Gender differences of symptom reporting and medical health
care utilization in the German population. Eur J Epidemiol 2000; 16: 511–518.
47 Bedogni B, Welford SM, Cassarino DS, et al. The hypoxic microenvironment of the skin contributes to
Akt-mediated melanocyte transformation. Cancer Cell 2005; 8: 443–454.
48 Gharib SA, Seiger AN, Hayes AL, et al. Treatment of obstructive sleep apnea alters cancer-associated
transcriptional signatures in circulating leukocytes. Sleep 2014; 37: 709–714, 714A–714T.
49 Weaver TE, Mancini C, Maislin G, et al. Continuous positive airway pressure treatment of sleepy patients with
milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP)
randomised clinical trial. Am J Respir Crit Care Med 2012; 186: 677–683.
50 Krachman S, Swift I, Vega ME. Comparison of positional therapy to CPAP in patients with positional obstructive
sleep apnea. In: de Vries N, Ravesloot M, van Maanen JP, eds. Positional Therapy in Obstructive Sleep Apnea.
Cham, Springer International Publishing, 2015.
51 Arzt M, Woehrle H, Oldenburg O, et al. Prevalence and predictors of sleep disordered breathing in patients with
stable chronic heart failure: the SchlaHF Registry. JACC Heart Fail 2016; 4: 116–125.
https://doi.org/10.1183/23120541.00036-2021 14You can also read
